Li Ning, He Fei, Gao Hang, Ge Ying, Fan Xiujun, Zhang Jian, Qi Hui, Ren Lili
Cytotherapy Laboratory, The Second Clinical Medical College (Shenzhen People's Hospital), Jinan University, Shenzhen, China.
The First Hospital of Jilin University, Jilin University, Changchun, China.
J Cell Physiol. 2020 Dec;235(12):9577-9588. doi: 10.1002/jcp.29766. Epub 2020 May 7.
Accumulated evidence has shown that pre-eclampsia (PE) is related to both maternal and utero-placental antiangiogenesis and inflammation. Remarkably, an elevated cell-free fetal DNA (cffDNA) level has been found in maternal circulation; however, it remains unclear whether this DNA can induce activation of cytosolic DNA sensor signaling pathways and lead to the development of PE. In this study, we found that trophoblast cells constitutively expressed the cytosolic DNA sensors, absent in melanoma 2 (AIM2) and interferon-inducible protein 16 (IFI16). The cffDNA and pro-inflammatory and antiangiogenic factors were present at higher concentrations in PE compared with the control group and correlated with the severity of PE. DNA stimulation significantly increased the AIM2 and IFI16 levels, consistent with the elevated AIM2 and IFI16 expression in women with PE, and elicited increased production of AIM2-mediated interleukin IL-8 (IL-8), IL-6 and CC chemokine ligand 2 (CCL2) and IFI16-mediated sEndoglin, sFlt-1 and CXCL10. Furthermore, enhancement of the inflammatory response was found to be induced by DNA exposure, but DNA exposure did not induce PE-like symptoms in pregnant mice. It is possible that elevated cffDNA could reflect the degree of placental damage and trigger cytosolic DNA sensor activation, which disrupts the immunity balance and, consequently, contributes to inflammatory and antiangiogenic responses. In conclusion, the results of this study suggest that circulating cffDNA levels are increased in preeclamptic women and act through AIM2 and IFI16 activation to promote the production of pro-inflammatory and antiangiogenic factors, which correlate with the severity of the disease, and may offer insights into the etiology and pathogenesis of PE.
越来越多的证据表明，子痫前期（PE）与母体及子宫胎盘的抗血管生成和炎症反应均有关联。值得注意的是，已发现母体循环中无细胞胎儿DNA（cffDNA）水平升高；然而，尚不清楚这种DNA是否能诱导胞质DNA传感器信号通路的激活并导致子痫前期的发生。在本研究中，我们发现滋养层细胞组成性表达胞质DNA传感器，即黑色素瘤缺失2（AIM2）和干扰素诱导蛋白16（IFI16）。与对照组相比，子痫前期患者中cffDNA以及促炎和抗血管生成因子的浓度更高，且与子痫前期的严重程度相关。DNA刺激显著提高了AIM2和IFI16的水平，这与子痫前期女性中AIM2和IFI16表达升高一致，并引发了AIM2介导的白细胞介素IL-8（IL-8）、IL-6和CC趋化因子配体2（CCL2）以及IFI16介导的可溶性内皮糖蛋白（sEndoglin）、可溶性血管内皮生长因子受体1（sFlt-1）和CXC趋化因子配体10（CXCL10）的产生增加。此外，发现DNA暴露可诱导炎症反应增强，但DNA暴露并未在妊娠小鼠中诱发类似子痫前期的症状。升高的cffDNA可能反映胎盘损伤程度并触发胞质DNA传感器激活，从而破坏免疫平衡，进而导致炎症和抗血管生成反应。总之，本研究结果表明，子痫前期女性循环中的cffDNA水平升高，并通过激活AIM2和IFI16促进促炎和抗血管生成因子的产生，这些因子与疾病严重程度相关，可能为子痫前期的病因和发病机制提供见解。
